Synthesis, biosimulation and pharmacological evaluation of benzimidazole derivatives with antihypertensive multitarget effect
Por:
Gutiérrez-Hernández A., Estrada-Soto S., Martínez-Conde C., Gaona-Tovar E., Medina-Franco J.L., Hernández-Núñez E., Hidalgo-Figueroa S., Castro-Moreno P., Ibarra-Barajas M., Navarrete-Vazquez G.
Publicada:
1 ene 2024
Ahead of Print:
1 jul 2024
Resumen:
In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT1R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1H NMR, 13C NMR and mass spectral data. Through biosimulation, compounds 1–7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of calcium channel. Molecular docking studies helped to understand at the molecular level the dual vasorelaxant effects with the recognition sites of the AT1R and the L-type calcium channel. In an in vivo spontaneously hypertensive rat model (SHR), intraperitoneally administration of compound 1 at 20 mg/kg resulted in a 25 % reduction in systolic blood pressure, demonstrating both ex vivo vasorelaxant action and in vivo antihypertensive multitarget efficacy. ©2024 Elsevier. © 2024 Elsevier Ltd
Filiaciones:
Gutiérrez-Hernández A.:
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Morelos, Cuernavaca, 62209, Mexico
Estrada-Soto S.:
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Morelos, Cuernavaca, 62209, Mexico
Martínez-Conde C.:
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Morelos, Cuernavaca, 62209, Mexico
Gaona-Tovar E.:
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Morelos, Cuernavaca, 62209, Mexico
Medina-Franco J.L.:
Grupo de investigación DIFACQUIM, Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, México City, 04510, Mexico
Hernández-Núñez E.:
Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados, IPN, Unidad Mérida, Yucatán, 97310, Mexico
Hidalgo-Figueroa S.:
CONAHCyT-División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica A. C., S. L. P, San Luis Potosí, 78216, Mexico
Castro-Moreno P.:
Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, 54090, Mexico
Ibarra-Barajas M.:
Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, 54090, Mexico
Navarrete-Vazquez G.:
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Morelos, Cuernavaca, 62209, Mexico
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